Population analysis and immunologic landscape of melanoma in people living with HIV indicate impaired antitumor immunity

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Abstract Purpose To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently shown worse outcomes than HIV-negative individuals (PLw/oH) with the same cancer. Experimental Design We analyzed electronic health records from 1,087 PLWH and 394,437 PLw/oH with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), with downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH). Results PLWH were diagnosed at a younger age, had greater representation of Hispanic and Black individuals, and showed reduced survival. They also had a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse post-ICI survival, even after balancing covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with increased transcription of immune checkpoints (PD1, LAG3) and reduced antigen-presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and surrounding microenvironments. Multiplex immunofluorescence demonstrated features of an exhausted CD8⁺ T cell compartment, including enrichment of PD1 int LAG3⁻ and PD1 int LAG3⁺ subpopulations, and a significant accumulation of myeloid-derived suppressor cells (CD11b⁺ HLA-DR⁻ CD33⁺). Conclusions Melanoma in PLWH is associated with distinct clinical and immunological features, including delayed ICI treatment, reduced survival, and an immunosuppressive microenvironment with exhausted CD8⁺ T cells and expanded myeloid-derived suppressor cells. These findings suggest that chronic HIV infection may impair antitumor immunity in melanoma. Targeting the pathways identified here may improve therapeutic responses and outcomes in this population. Statement of translational relevance This study reveals critical barriers to effective melanoma treatment in people living with HIV (PLWH). Despite receiving immune checkpoint inhibitors (ICIs), PLWH face delayed therapy initiation, a greater likelihood of brain metastases, and significantly higher long-term mortality, even after adjusting for demographic covariates. Transcriptional immune profiling further uncovers a tumor microenvironment enriched in immunosuppressive myeloid-derived suppressor cells and CD8⁺ T cell populations with features of exhaustion. These findings suggest that poorer outcomes in PLWH stem not only from delayed care, but also from distinct targetable mechanisms of immune dysfunction. For example, strategies to reverse MDSC accumulation in the tumor or tailored ICI regimens could enhance immune responsiveness and improve treatment efficiency. By defining the clinical and immunological features of this population, this work highlights opportunities for precision immunotherapy tailored to PLWH with melanoma, with direct implications for improving survival and reducing disparities.

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